Chronic kidney disease, affecting over 26 million Americans, frequently leads to kidney failure requiring either dialysis or kidney transplant. Each year more than 100,000 individuals develop kidney failure and nearly 500,000 receive dialysis or kidney transplants at an annual cost of $30 billion dollars. The three leading causes of kidney failure requiring dialysis or kidney replacement for survival are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end stage renal disease (ESRD) compared to their white counterparts. FSGS is the leading cause of primary nephritic syndrome in adults and the leading cause of end-stage renal disease (ESRD) in children. FSGS represents a syndrome that includes variants that are idiopathic and are associated with reduced nephron numbers, hypertension, and HIV-1 infection. African-Americans are at a four-fold risk of developing idiopathic FSGS, and at a 50 to 70-fold increased risk for HIV-associated FSGS, also known as HIV-associated nephropathy (HIVAN). HIVAN is the third leading cause of kidney failure in African American adult men. In collaboration with the Kidney Disease Section, NIDDK, patients have been enrolled from 13 extramural sites. The study comprises biopsy-proven sporadic FSGS or HIV-1-associated nephropathy (HIVAN) cases with biopsy-proven collapsing glomerulosclerosis and 919 donor controls. More than 60% of end stage kidney disease is associated with diabetes and hypertension, and approximately 30% with glomerulopathies, mainly due to FSGS. We have have also entered into collaborations to investigate the role of host genetic factors in other etiologies of kidney disease (e.g., sickle cell anemia nephritis, pre-elampsia, lupus, diabetes, and hypertension). Structural proteins expressed in podocytes are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space in the kidney. NPHS2 encodes podocin, a protein expressed exclusively on the glomerular podocyte. A point mutation in the NPHS2 gene causes an amino acid change from arginine to glutamine at position 138 (R138Q) in the podocin protein. Homozygotes for this polymorphism develop childhood FSGS, but we have shown for the first time that 138Q carriers are at a 5-6 fold increased risk of developing FSGS. In collaborative study we have investigated the possible role of mutations in the PDSS2 gene in susceptibility to FSGS. The mouse ortholog of PDSS2 has been shown to play a role in kidney disease in a promising mouse model for FSGS. We discovered that individuals in the European American study group with a specific haplotype have a 5-6 fold increased chance of developing FSGS. The Wilms tumor gene (WT-1) is important for nephrogenesis and gonadol growth and mutations in WT-1 lead to glomerular scarring. Variants in the WT-1 gene and the adjacent WIT-1 gene were shown to be risk factors for FSGS. There is still reason to believe that additional genes and/or environmental factors affect susceptibility to FSGS and collapsing glomerulopathy as these variant alleles explain only a small fraction of FSGS disease incidence. Accomplishments Because of the increased risk of chronic and end stage kidney disease in African Americans, we hypothesized that the increased predilection for kidney disease among African-descent individuals is due to the presence of one or more causal alleles more frequent in individuals with African ancestry. Using mapping by admixture disequilibrium (MALD) followed by fine mapping, we recently identified MYH9 on Chromosome 22 as a main effect gene for sporadic and HIV-1-related FSGS and nondiabetic kidney disease in African Americans. In two studies, we showed that a genetic locus, MYH9, explains much of the increased risk in African Americans for sporadic, HIV-associated collapsing FSGS and hypertensive kidney failure suggesting a shared genetic etiology for these forms of kidney disease. The strongest haplotype and risk alleles have frequencies of 60% or more in African Americans and less than 4% in European Americans. Our finding substantially explained the excess burden in African Americans for these major kidney diseases and provide a genetic basis for a major USA and global health disparity. We have continued to examine the role of MYH9 risk variants in other forms of kidney diseases and in larger study groups to more precisely assess risk. In collaborative studies we have shown and published that MYH9 is a predictor of kidney failure historically attributable to hypertension (OR range 1.5-3) and to kidney failure in a setting of diabetes (OR range 1.2-1.4). The results of these studies indicate that MYH9 underlies a portion of hypertensive and diabetic ESRD in African Americans. This suggests that a subset of African Americans with type 2 diabetes and hypertension co-incident with nephropathy have primary MYH9-related kidney disease (e.g. FSGS or global glomerulosclerosis). Before the discovery of MYH9 as a renal susceptibility gene, it was widely held that essential hypertension was the inciting cause of nephrosclerosis and progression to ESRD, but this new evidence suggests that at least part of hypertension-associated renal failure may be due underlying MYH9-related kidney disease. This also explains, in part, why intensive treatment to control hypertension has proven ineffective in hypertensive African Americans. This also provides an explanation for why kidney disease with disparate etiologies (e.g., diabetic, hypertension, HIV infection) clustered in families. To identify the functional genetic variation we have used a two stage re-sequencing strategy. In the first stage we re-sequenced MYH9 exons from 19 persons carrying risk haplotypes but failed to identify codon-changing mutations that could account for the associations with kidney disease. In the next stage we re-sequenced genomic DNA from both introns and exons from 39 individuals carrying MYH9 risk protective and susceptible risk haplotypes. Again we failed to discover codon-changing mutations that could account for the signal. These results have led us to focus our efforts on transcript expression differences in either the levels of transcripts expressed or in splice isoforms. Dense mapping of &lt;i&gt;MYH9&lt;/i&gt;is now being performed to identify the causal functional variation responsible for podocyte impairment predisposing to kidney disease. It is anticipated that these findings will lead to more targeted approaches for the treatment of chronic kidney disease to prevent or delay progression to kidney failure. We also expect that this finding will have a major impact on public health--genetic screening will be useful in identifying individuals at greater risk for kidney disease and in counseling genetically vulnerable individuals in modifiable risk reduction behaviors. While not everyone with MYH9 risk alleles will develop chronic kidney disease, the likelihood of disease is increased by 100-500% in these individuals.